Sulphur containing pyrazole derivatives as selective cannabinoid CB1  receptor antagonists

ABSTRACT

The present invention relates to sulphur containing pyrazole derivatives, and their S-oxidized active metabolites, as selective cannabinoid CB 1  receptor antagonists having a high CB 1 /CB 2  receptor subtype selectivity, to methods for the preparation of these compounds, to novel intermediates useful for the synthesis of these pyrazole derivatives, to pharmaceutical compositions comprising one or more of these pyrazole derivatives as active ingredients, as well as to the use of these pharmaceutical compositions for the treatment of psychiatric and neurological disorders. The compounds have the general formula (I) 
                         
wherein the symbols have the meanings given in the specification.

This is a divisional of application Ser. No. 11/754,544, filed May 29,2007 now U.S. Pat. No. 7,786,144, and claims the benefit of U.S.Provisional Application No. 60/809,367, filed May 31, 2006, all of whichare incorporated herein by reference.

Pyrazole derivatives having CB receptor affinity are known from severalpatent applications, (including WO 98/43636, WO 98/43635, WO2005/000820, WO2006/030124, WO 2004/099157, EP 0876350 and US2006/0100208), and other publications (Lan et al., J. Med. Chem. 1999,42, 769-776; Francisco et al., J. Med. Chem. 2002, 45, 2708-2719;Katoch-Rouse et al., J. Med. Chem. 2003, 46, 642-645; Meschler et al.,Biochem. Pharmacol. 2000, 60, 1315-1323; Matthews et al., J. LabelledCompds. Radiopharm. 1999, 42, 589-596). CB₁ receptor antagonists, inparticular SR141716A, now known as rimonabant, and their potentialtherapeutic applications, have been the subject of several reviews(Boyd, S. T. and Fremming, B. A., Ann. Pharmacother. 2005, 39, 684-690;Sorbera, L. A. et al., Drugs Fut. 2005, 30, 128-137; Carai, M. A. M. etal., Life Sc. 2005, 77, 2339-2350; Lange, J. H. M. and Kruse, C. G.,Curr, Opin, Drug Discovery Dev. 2004, 7, 498-506, Lange, J. H. M. andKruse, C. G., Drug Discov. Today 2005, 10, 693-702; Hertzog, D. L.,Expert Opin. Ther. Patents 2004, 14, 1435-1452; Smith, R. A. and Fathi,Z., IDrugs 2005, 8, 53-66; Thakur, G. A. et al., Mini-Rev. Med. Chem.2005, 5, 631-640; Padgett, L. W., Life Sc. 2005, 77, 1767-1798;Muccioli, G. G. et al., Curr. Med. Chem. 2005, 12, 1361-1394, Muccioli,G. G. and Lambert, D. M., Expert Opin. Ther. Patents 2006, 16,1405-1423; Reggio, P. H., Curr. Pharm. Des. 2003, 9, 1607-1633; Adam, J.et al., Progress in Med. Chem. 2006, 44, 207-329, Eds. King and Lawton,Elsevier, Amsterdam). The abovementioned patent applications andarticles disclose a number of CB₁/CB₂ receptor subtype selectivereceptor antagonists. Cannabinoid (CB) receptors are part of theendocannabinoid system, which is involved in neurological, psychiatric,cardiovascular, gastrointestinal, reproductive, and eating disorders aswell as in cancer (De Petrocellis, L. et al., Br. J. Pharmacol. 2004,141, 765-774; Di Marzo, V. et al., Nature Rev. Drug Discov. 2004, 3,771-784; Lambert, D. M. and Fowler, C. J., J. Med. Chem. 2005, 48,5059-5087; Vandevoorde, S. and Lambert, D. M., Curr. Pharm. Des. 2005,11, 2647-2668; Centonze, D. et al., Trends Pharmacol. Sci. 2007, 28,180-187).

CB₁ receptor modulators have several potential therapeutic applications,such as their use as medicaments for treating psychosis, anxiety,depression, attention deficits, memory disorders, cognitive disorders,appetite disorders, obesity, addiction, appetence, drug dependence,neurodegenerative disorders, dementia, dystonia, muscle spasticity,tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke,Parkinson's disease, Alzheimer's disease, epilepsy, Huntington'sdisease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy,craniocerebral trauma, stroke, spinal cord injury, neuroinflammatorydisorders, plaque sclerosis, viral encephalitis, demyelinisation relateddisorders, as well as for the treatment of pain disorders, includingneuropathic pain disorders, septic shock, glaucoma, diabetes, cancer,emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea,sexual disorders, impulse control disorders, and cardiovasculardisorders.

CB₂ receptors occur predominantly in the immune system (spleen, tonsils,immune cells) as well as in microglial cells and astrocytes and haverecently also been found in the central nervous system brainstem andcerebellum (Van Sickle et at., Science 2005, 310, 329-332; Ashton etal., Neuroscience Lett. 2006, 396, 113-116).

Potent CB₁ receptor modulators having low CB₂ receptor affinity (i.e.,compounds having a high CB₁/CB₂ receptor subtype selectivity) areadvantageous compounds as compared to non-selective or less selectivecannabinoid receptor modulators as they will be devoid of undesired CB₂receptor mediated side-effects, such as immunologic or inflammatoryrelated side-effects or effects on neuropathic pain perception.

A goal of the present invention was to further develop orally active CB₁receptor antagonists with a high CB₁/CB₂ receptor subtype selectivity.

Certain pyrazole derivatives of formula (I), in which X (See below)represents a CH₂ group, are known to be CB₁ receptor antagonists,Surprisingly, it was found that replacement of this CH₂ group by asulphur atom results in compounds that not only are CB₁/CB₂ receptorsubtype selective CB₁ receptor antagonists, but that are more potentthan their non-sulphur containing analogs when tested orally in an invivo CB₁ receptor mediated pharmacological assay. Compounds of thegeneral formula (I) wherein X represents a S═O or a SO₂ group can beconsidered metabolites of the compounds of the general formula (I)wherein X represents a sulphur atom. Such compounds of the generalformula (I) wherein X represents a S═O (sulfoxide) or a SO₂ (sulfone)group were also surprisingly found to elicit significant CB₁ receptoraffinities and as a result can be considered active S-oxidizedmetabolites of the compounds of the general formula (I) wherein Xrepresents a sulphur atom. In general, the formation of activemetabolites is known to enhance the potency of therapeutics in vivo.Active metabolites of the general formula (I) wherein X represents a S═Oor a SO₂ group are part of the present invention. Cytochrome P450 is animportant endogenous enzyme which is involved in such metabolicoxidations of alkyl sulfides into the corresponding sulfoxides andsulfones (Denisov et al., Chem. Rev. 2005, 105, 2253-2277; Nnane et al.,Eur. J. Drug Metab. Pharmacokin. 2001, 26, 17-24).

The present invention relates to compounds of the general formula (I):

wherein:

R₁ represents H, Cl or Br,

R₂ represents Cl or Br,

X represents a sulphur atom, a sulfoxide (S═O) or a sulfone (SO₂)moiety,

Y represents a methyl or an ethyl group, and

n can have the value 1, 2 or 3,

and tautomers, stereoisomers, prodrugs and N-oxides thereof, andisotopically-labelled compounds of formula (I), as well aspharmacologically acceptable salts, hydrates and solvates of saidcompounds of formula (I) and its tautomers, stereoisomers, prodrugs,N-oxides or isotopically-labelled analogs.

All sulfoxides within this invention contain a center of chirality. Theinvention relates to racemates, mixtures of diastereomers, as well asthe individual stereoisomers of the compounds having formula (I). Theinvention also relates to the E isomer, Z isomer and E/Z mixtures ofcompounds having formula (I).

The invention also relates to compounds of the general formula (I) inwhich R₁ and R₂ represent Cl, Y represents a methyl group, X has themeanings as given above, and n represents 1 or 2.

Additionally, the invention relates to the compounds represented by theformula:

Due to the potent CB₁ antagonistic or inverse agonist activity, thecompounds according to the invention are suitable for use in thetreatment of psychiatric disorders, such as psychosis, anxiety,depression, attention deficits, memory disorders, cognitive disorders,appetite disorders, obesity, in particular juvenile obesity and druginduced obesity, addiction, appetence, drug dependence and neurologicaldisorders, such as neurodegenerative disorders, dementia, dystonia,muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic braininjury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy,Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebralapoplexy, cranio-cerebral trauma, stroke, spinal cord injury,neuroinflammatory disorders, plaque sclerosis, viral encephalitis,demyelinisation related disorders, as well as for the treatment of paindisorders, including neuropathic pain disorders, and other diseasesinvolving cannabinoid neurotransmission, including the treatment ofseptic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma,respiratory diseases, gastrointestinal disorders, gastric ulcers,diarrhoea, sexual disorders, impulse control disorders andcardiovascular disorders.

The cannabinoid receptor modulating activity of the compounds of theinvention makes them useful in the treatment of obesity, juvenileobesity and drug induced obesity, for example, when used in combinationwith lipase inhibitors. Specific examples of compounds which can be usedin such combination preparations include, but are not restricted to, thesynthetic lipase inhibitor orlistat, lipase inhibitors isolated frommicro organisms such as lipstatin (from Streptomyces toxytricini),ebelactone B (from Streptomyces aburaviensis), synthetic derivatives ofthese compounds, as well as extracts of plants known to possess lipaseinhibitory activity, for instance extracts of Alpinia officinarum orcompounds isolated from extracts such as 3-methylethergalangin (from A.officinarum).

The invention also embraces:

a pharmaceutical composition for treating, for example, a disorder orcondition treatable by blocking cannabinoid-CB1 receptors, thecomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier;

a method of treating a disorder or condition treatable by blockingcannabinoid-CB1 receptors, the method comprising administering to amammal in need of such treatment a compound of formula (I) or apharmaceutically acceptable salt thereof;

a pharmaceutical composition for treating, for example, a disorder orcondition selected from the group of disorders listed herein;

a method of treating a disorder or condition selected from the group ofdisorders listed herein, the method comprising administering to a mammalin need of such treatment a compound of formula (I) or apharmaceutically acceptable salt thereof;

a pharmaceutical composition for treating the disorders listed herein,the composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof, and

a pharmaceutically acceptable carrier;

a method for treating the disorders listed herein, the method comprisingadministering to a patient in need of such treatment a compound offormula (I) or a pharmaceutically acceptable salt thereof; and

a method of antagonizing a cannabinoid-CB1 receptor that comprisesadministering to a subject in need thereof, an effective amount of acompound of formula (I).

The invention also provides for the use of a compound or salt accordingto formula (I) for the manufacture of a medicament.

The invention further relates to combination therapies wherein acompound of the invention, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition or formulation comprising acompound of the invention, is administered concurrently or sequentiallyor as a combined preparation with another therapeutic agent or agents,for treating one or more of the conditions listed. Such othertherapeutic agent(s) may be administered prior to, simultaneously with,or following the administration of the compounds of the invention.

The invention also provides compounds, pharmaceutical compositions,kits, and methods for treating the disorders listed herein, the methodscomprising administering to a patient in need of such treatment acompound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of the invention possess cannabinoid-CB₁ antagonisticactivity. The antagonizing activity of the compounds of the invention isreadily demonstrated, for example, by using one or more of the assaysdescribed herein or known in the art.

The invention also provides methods of preparing the compounds of theinvention and the intermediates used in those methods.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures, and individualdiastereomers.

Depending on the nature of the various substituents, the molecule canhave additional asymmetric centers. Each such asymmetric center willindependently produce two optical isomers. All of the possible opticalisomers and diastereomers, in mixtures and as pure or partially purifiedcompounds, belong to this invention. The present invention comprehendsall such isomeric forms of these compounds. Formula (I) shows thestructure of the class of compounds without preferred stereochemistry.The independent syntheses of these diastereomers, or theirchromatographic separations, may be achieved by methods known in the artby appropriate modification of the methodology disclosed therein. Theirabsolute stereochemistry may be determined by x-ray crystallography ofcrystalline products or crystalline intermediates, which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. Racemic mixtures of thecompounds can be separated into the individual enantiomers by methodswell-known in the art, such as the coupling of a racemic mixture ofcompounds to an enantiomerically pure compound to form a diastereomericmixture, followed by separation of the individual diastereomers bystandard methods, such as fractional crystallization or chromatography.The coupling often consists of the formation of salts using anenantiomerically pure acid or base, for example(−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaricacid. The diastereomeric derivatives may then be converted to the pureenantiomers by cleavage of the added chiral residue. The racemic mixtureof the compounds can also be separated directly by chromatographicmethods utilizing chiral stationary phases by methods well-known in theart. Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well-known in the art.

Cis and trans isomers of the compound of formula (I), or apharmaceutically acceptable salt thereof, also belong to the invention,as well as tautomers of the compounds of formula (I) or apharmaceutically acceptable salt thereof.

Some of the crystalline forms for the compounds may exist as polymorphsand such polymorphs are intended to belong to the invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents. Such solvates also fall within thescope of this invention. Isotopically-labeled compounds of formula (I)or pharmaceutically acceptable salts thereof, including compounds offormula (I) isotopically-labeled to be detectable by PET or SPECT, alsofall within the scope of the invention. The same applies to compounds offormula (I) labeled with [¹³C]—, [¹⁴C]—, [³H]—, [¹⁸F]—, [¹²⁵I]— or otherisotopically enriched atoms, suitable for receptor binding or metabolismstudies.

Definitions of Chemical and Other Terms

The term ‘alkyl’ refers to straight or branched saturated hydrocarbonradicals. ‘Alkyl(C₁₋₃)’ for example, means methyl, ethyl, n-propyl orisopropyl, and ‘alkyl(C₁₋₄)’ means ‘methyl, ethyl, n-propyl, isopropyl,n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyr. The term ‘aryl’embraces monocyclic or fused bicyclic aromatic or hetero-aromaticgroups, including but not limited to furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, imidazo[2,1-b][1,3]thiazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,3,5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl,benzo[b]furanyl, 1,2,3,4-tetrahydro-naphtyl,1,2,3,4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo[b]thienyl,2,3-dihydro-1,4-benzodioxin-5-yl, benzimidazolyl, benzothiazolyl,benzo[1,2,5]thia-diazolyl, purinyl, quinolinyl, isoquinolinyl,phtalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, naphthyl,pteridinyl or azulenyl. ‘Halo’ or ‘Halogen’ means chloro, fluoro, bromoor iodo; ‘hetero’ as in ‘heteroalkyl, heteroaromatic’ etc. meanscontaining one or more N, O or S atoms. ‘Heteroalkyl’ includes alkylgroups with heteroatoms in any position, thus including N-bound O-boundor S-bound alkyl groups. The terms “oxy”, “thio” and “carbo” as usedherein as part of another group respectively refer to an oxygen atom, asulphur atom, and a carbonyl (C═O) group, serving as linker between twogroups, such as for instance hydroxyl, oxyalkyl, thioalkyl,carboxyalkyl, etc. The term “amino” as used herein alone, or as part ofanother group, refers to a nitrogen atom that may be either terminal, ora linker between two other groups, wherein the group may be a primary,secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom,one hydrogen atom bonded to the nitrogen atom and no hydrogen atomsbonded to the nitrogen atom, respectively) amine. The terms “sulfinyl”and “sulfonyl” as used herein as part of another group respectivelyrefer to an —SO— or an —SO₂— group.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group that departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

N-oxides of the compounds mentioned above belong to the invention.Tertiary amines may or may not give rise to N-oxide metabolites. Theextent to which N-oxidation takes place varies from trace amounts to anear quantitative conversion. N-oxides may be more active than theircorresponding tertiary amines, or less active. While N-oxides can easilybe reduced to their corresponding tertiary amines by chemical means, inthe human body this happens to varying degrees. Some N-oxides undergonearly quantitative reductive conversion to the corresponding tertiaryamines, in other cases conversion is a mere trace reaction, or evencompletely absent (Bickel, M. H., “The pharmacology and biochemistry ofN-oxides,” 1969 Pharmacological Reviews, 21(4): 325-355).

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value. Throughout the description and theclaims of this specification the word “comprise” and variations of theword, such as “comprising” and “comprises,” are used and are notintended to exclude other additives, components, integers or steps.

Any compound metabolized in vivo to provide the bioactive agent (i.e.,the compound of formula (I)) is a prodrug within the scope and spirit ofthe application. Prodrugs are therapeutic agents, inactive per se buttransformed into one or more active metabolites. Thus, in the methods oftreatment of the present invention, the term “administering” shallencompass treating the various disorders described with the compoundspecifically disclosed, or with a compound not specifically disclosed,but that converts to the specified compound in vivo after administrationto the patient. Prodrugs are bioreversible derivatives of drug moleculesused to overcome specific barriers to the utility of the parent drugmolecule. These barriers include, but are not limited to, solubility,permeability, stability, presystemic metabolism and targetinglimitations (Bundgaard, H. ed., Design of Prodrugs, Elsevier, 1985;King, F. D. ed., Medicinal Chemistry: Principles and Practice, 1994,215; Stella, J., “Prodrugs as therapeutics,” 2004 Expert Opin. Ther.Patents, 14(3):277-280; Ettmayer, P. et al., “Lessons learned formmarketed and investigational prodrugs,” 2004 J. Med. Chem., 47:2393-2404; Järvinen, T. et al., “Design and Pharmaceutical applicationsof prodrugs,” 733-796 in Drug Discovery Handbook, S. C. Gad, ed., 2005,John Wiley & Sons, inc., USA). Prodrugs, i.e., compounds that whenadministered to humans by any known route are metabolised to compoundshaving formula (I), belong to the invention. In particular, this relatesto compounds with primary or secondary amino or hydroxy groups. Suchcompounds can be reacted with organic acids to yield compounds havingformula (I) wherein an additional group is present that is easilyremoved after administration, for instance, but not limited to amidine,enamine, a Mannich base, a hydroxyl-methylene derivative, anO-(acyloxymethylene carbamate) derivative, carbamate, ester, amide orenaminone.

The term “composition” as used herein encompasses a product comprisingspecified ingredients in predetermined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. In relation topharmaceutical compositions, this term encompasses a product comprisingone or more active ingredients, and an optional carrier comprising inertingredients, as well as any product that results, directly orindirectly, from combination, complexation or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. In general, pharmaceutical compositions areprepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. The pharmaceutical composition includes enough of theactive object compound to produce the desired effect upon the progressor condition of diseases. Accordingly, the pharmaceutical compositionsof the present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier.

Within the context of this application, the term ‘combinationpreparation’ comprises both true combinations, meaning compounds of theinvention and other medicaments physically combined in one preparationsuch as a tablet or injection fluid, as well as ‘kit-of-parts’,comprising compounds of the invention and a lipase inhibitor in separatedosage forms, together with instructions for use, optionally withfurther means for facilitating compliance with the administration of thecomponent compounds, e.g. label or drawings. With true combinations, thepharmacotherapy by definition is simultaneous. The contents of‘kit-of-parts’, can be administered either simultaneously or atdifferent time intervals. Therapy being either concomitant or sequentialwill be dependant on the characteristics of the other medicaments used,characteristics like onset and duration of action, plasma levels,clearance, etc., as well as on the disease, its stage, andcharacteristics of the individual patient.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The affinity of the compounds of the invention for cannabinoid receptorswas determined as described below. From the binding affinity measuredfor a given compound of formula (I), one can estimate a theoreticallowest effective dose. At a concentration of the compound equal to twicethe measured K_(i)-value, nearly 100% of the cannabinoid-CB₁ receptorslikely will be occupied by the compound. Converting that concentrationto mg of compound per kg of patient yields a theoretical lowesteffective dose, assuming ideal bioavailability. Pharmacokinetic,pharmacodynamic, and other considerations may alter the dose actuallyadministered to a higher or lower value. The dosage expedientlyadministered is 0.001-1000 mg/kg, preferably 0.1-100 mg/kg of patient'sbodyweight.

The term “therapeutically effective amount” as used herein refers to anamount of a therapeutic agent to treat or prevent a condition treatableby administrating a composition of the invention. That amount is theamount sufficient to exhibit a detectable therapeutic, preventative orameliorative response in a tissue system, animal or human. The effectmay include, for example, treating or preventing the conditions listedherein. The precise effective amount for a subject will depend upon thesubject's size and health, the nature and extent of the condition beingtreated, recommendations of the treating physician (researcher,veterinarian, medical doctor or other clinician), and the therapeutics,or combination of therapeutics, selected for administration. Thus, it isnot useful to specify an exact effective amount in advance.

The term “pharmaceutically acceptable salt” refers to those salts thatare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. They can be prepared in situwhen finally isolating and purifying the compounds of the invention, orseparately by reacting them with pharmaceutically acceptable non-toxicbases or acids, including inorganic or organic bases and inorganic ororganic acids.

The term “treatment” as used herein refers to any treatment of amammalian, preferably human condition or disease, and includes: (1)preventing the disease or condition from occurring in a subjectpredisposed to the disease, but not yet diagnosed as having it, (2)inhibiting the disease or condition, i.e., arresting its development,(3) relieving the disease or condition, i.e., causing the condition toregress, or (4) stopping the symptoms of the disease.

As used herein, the term “medical therapy” includes prophylactic,diagnostic and therapeutic regimens carried out in vivo or ex vivo onhumans or other mammals. The term “subject” as used herein, refers to ananimal, preferably a mammal, most preferably a human, who has been theobject of treatment, observation or experiment.

EXAMPLES Example 1 Analytical Methods

¹H NMR spectra were recorded on a Bruker 400 MHz or a 300 MHz instrumentusing CDCl₃ as solvent with tetramethylsilane as an internal standard.¹³C NMR spectra were recorded on a Bruker instrument (100 MHz) usingCDCl₃ as solvent. Chemical shifts are given in ppm (δ scale) downfieldfrom tetramethylsilane. Coupling constants (J) are expressed in Hz.Flash chromatography was performed using silica gel 60 (0.040-0.063 mm,Merck). Column chromatography was performed using silica gel 60(0.063-0.200 mm, Merck). Melting points were recorded on a Büchi B-545melting point apparatus.

Example 2 General Aspects of Syntheses

The synthesis of compounds having formula (I) is outlined in Scheme 1.The synthesis of the intermediates having formula (II) proceedsanalogously to published procedures (Lan, 1999; Francisco, 2002;Katoch-Rouse 2003). The carboxylic acid of general formula (II) whereinR₁ and R₂ have the abovementioned meaning can be brominated to thecorresponding 4-bromo derivative (III) using a brominating agent such asbromine in an inert organic solvent such as dichloromethane. This bromoderivative (III) wherein R₁ and R₂ have the abovementioned meaning canbe treated with a strong base such as n-butyllitium in an inertanhydrous organic solvent such as tetrahydrofuran and subsequentlyreacted with a sulphur-derived electrophile YSSY wherein Y represents amethyl or ethyl group to afford a compound of general formula (IV)wherein R₁, R₂ and Y have the abovementioned meaning, R₄ is a hydrogenatom and X represents a sulphur atom. This compound of general formula(IV) can be converted to the corresponding ester of general formula (V)wherein R₁, R₂ and Y have the abovementioned meaning, R₃ represents alinear C₁₋₃ alkyl group (methyl, ethyl or n-propyl), and X represents asulphur atom. This ester of general formula (V) can be oxidised with onemolar equivalent of an oxidizing reagent such as meta-chloroperbenzoicacid to give the corresponding sulfinyl analogue. Alternatively,reaction of a compound of general formula (V) with two or more molarequivalents of meta-chloroperbenzoic acid can convert the sulfanylmoiety to the corresponding sulfonyl moiety. The ester of generalformula (V) wherein R₁, R₂ and Y have the abovementioned meaning and Xrepresents a sulfoxide or sulfone moiety can be hydrolysed—preferablyunder acidic conditions—to give the corresponding carboxylic acid (VI).The resulting compound of general formula (VI) can be coupled with anamine in the presence of an activating or coupling reagent to give acompound of general formula (I), wherein R₁, R₂, Y and n have theabovementioned meaning and X represents a sulfoxide (S═O) moiety or asulfone (SO₂) moiety.

Alternatively, a compound of general formula (IV) wherein R₁, R₂ and Yhave the abovementioned meaning and X represents a sulphur atom can becoupled with an amine in the presence of an activating or couplingreagent to give a compound of general formula (I), wherein R₁, R₂, Y andn have the abovementioned meaning and X represents a sulphur atom

Alternatively, an ester derivative having formula (V) can be reacted ina so-called Weinreb amidation reaction with an amine to give a compoundof general formula (I), wherein R₁, R₂, Y and n have the abovementionedmeaning and X represents a sulphur atom or a sulfoxide (S═O) moiety or asulfone (SO₂) moiety. Such Weinreb amidation reactions can be promotedby the use of trimethylaluminum Al(CH₃)₃ (Levin, et al., Synth common1982, 12, 989-993). Activating and coupling methods of amines tocarboxylic acids are well documented (Bodanszky, M. and A. Bodanszky,“The Practice of Peptide Synthesis,” Springer-Verlag, New York, 1994;Akaji, K. et al., Tetrahedron Lett. 1994, 35, 3315-3318; Albericio, F.et al., Tetrahedron Lett. 1997, 38, 4853-4856; Montalbetti, C. A. G. N.and V. Falque, Tetrahedron 2005, 61, 10827-10852).

An alternative synthesis of compounds having formula (I) is outlined inScheme 2. The bromoacetophenone derivative of general formula (VII),wherein R₂ has the abovementioned meaning, can be reacted with acompound of general formula NaS—Y to the corresponding1-aryl-2-(alkylsulfanyl)ethanone derivative (VIII) in an inert organicsolvent such as methanol. This 1-aryl-2-(alkylsulfanyl)ethanonederivative (VIII) wherein R₂ has the abovementioned meaning can bereacted with an oxalic ester derivative of general formula (IX) in thepresence of a base such as sodium alkanoate in an inert anhydrousorganic solvent, followed by a reaction with an arylhydrazine (X) or asalt thereof, wherein R₁ has the abovementioned meaning to give an esterof general formula (V) wherein R₁, R₂ and Y have the abovementionedmeaning, R₃ represents a linear C₁₋₃ alkyl group (methyl, ethyl orn-propyl) and X represents a sulphur atom. This ester of general formula(V) can be hydrolyzed under basic conditions, for example with lithiumhydroxide, to give the corresponding carboxylic acid of general formula(IV) or its alkali-element (such as lithium, sodium or potassium) salt.This carboxylic acid or carboxylic acid alkali-element salt of generalformula (IV) wherein R₁, R₂ and Y have the abovementioned meaning and Xrepresents a sulphur atom can be coupled with an amine in the presenceof an activating or coupling reagent in an inert organic solvent such asdimethylformamide to give a compound of general formula (I), wherein R₁,R₂, Y and n have the abovementioned meaning and X represents a sulphuratom. This compound of general formula (I), wherein R₁, R₂, Y and n havethe abovementioned meaning and X represents a sulphur atom can beoxidised with one molar equivalent of meta-chloroperbenzoic acid to givethe corresponding sulfinyl analogue (X represents a S═O group).Alternatively, reaction of a compound of general formula (I) wherein Xrepresents a sulphur atom with two or more molar equivalents ofmeta-chloroperbenzoic acid can convert the sulfanyl moiety in (I) to thecorresponding sulfonyl moiety.

The selection of the particular synthetic procedures depends on factorsknown to those skilled in the art, including factors such as thecompatibility of functional groups with the reagents used, thepossibility to use protecting groups, catalysts, activating and couplingreagents and the ultimate structural features present in the finalcompound being prepared.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by mixing a compound ofthe present invention with a suitable acid, for instance an inorganicacid such as hydrochloric acid, or with an organic acid. Hydrates can beobtained using standard procedures well known in the art, for example bycrystallization or evaporation from a water-containing (non-anhydrous)organic solvent.

Example 3 Syntheses of Specific Compounds

Compound 1

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(m.p. 185-187° C.) was obtained from methyl5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylate viaester hydrolysis under basic conditions (methanol, aqueous KOH).

4-Bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylicacid

To a magnetically stirred solution of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(20.0 g, 54.5 mmol) in dichloromethane (400 ml) was slowly added bromine(5.62 ml, 109 mmol) and the resulting mixture was reacted for 16 hoursat room temperature. Diethyl ether (400 ml) and excess aqueous saturatedNaHCO₃ solution were successively added. The organic layer wasseparated, twice washed with aqueous saturated NaHCO₃ solution andsubsequently washed with brine, dried over MgSO₄, filtered andconcentrated to give4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylicacid (19.77 gram, 81% yield). Melting point: 222-224° C.

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylicacid

To a magnetically stirred solution of4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylicacid (5.00 g, 11.2 mmol) in anhydrous tetrahydrofuran (THF) (250 ml) wasadded n-butyllithium (15/5 ml, 1.6 M solution, 25.2 mmol) and theresulting solution was stirred for 15 minutes under N₂ at −78° C. Asolution of dimethyl disulfide (CH₃S)₂ (3.16 g, 33.6 mmol) in anhydrousTHF (20 ml) was added by syringe and the resulting solution was stirredat −78° C. overnight. The reaction mixture was quenched with excesswater and the resulting solution was extracted with diethyl ether. Thediethyl ether layer was washed with water, dried over MgSO₄, filteredand concentrated to give crude5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylicacid which was further purified using flash chromatography(eluant:dichloromethane/methanol=95/5 (v/v)) followed by another flashchromatographic purification (eluant:dichloromethane/ethanol=95/5 (v/v))to give5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylicacid (2.75 g) which was immediately converted in the next reaction step.

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide

To a magnetically stirred solution of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylicacid (4.69 g, 11.3 mmol) in dichloromethane (100 ml) was successivelyadded 7-aza-1-hydroxybenzotriazole (HOAt) (2.2 g, 16.0 mmol),(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (3.1g, 16.1 mmol) and 1-aminopiperidine (1.6 gram, 16.0 mmol). Afterstirring for 16 h, the resulting mixture was successively washed withwater (3×), dried over Na₂SO₄, filtered and concentrated to give a crudesolid. This crude solid was further purified by flash chromatography(silica gel, EtOAc/heptane=22178 (v/v)) and trituration withn-heptane/methanol to give5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide:compound 1 (0.55 gram, 10% yield). Melting point: 172.4-174.5° C. ¹H-NMR(CDCl₃, 400 MHz) δ 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H), 2.40 (s, 3H),2.83-2.95 (m, 4H), 7.15 (br d, J=8 Hz, 2H), 7.28-7.35 (m, 4H), 7.42 (brd, J=2 Hz, 1H), 7.94 (br s, 1H). ¹³C-NMR (CDCl₃, 100 MHz) δ 20.03,23.32, 25.29, 57.02, 113.66, 126.20, 127.99, 128.74, 130.36, 130.48,131.24, 132.85, 135.59, 135.64, 136.41, 147.08, 147.30, 158.62.

Compound 2

1-(4-Chlorophenyl)-2-(methylsulfanyl)ethanone

To a magnetically stirred solution of bromo-4-chloro-acetophenone (16.8g, 72 mmol) in methanol (200 ml) was added NaSCH₃ (5.23 g, 72 mmol) togive an exothermic reaction. The resulting mixture was reacted for 2hours at room temperature, concentrated and suspended in dichloromethane(150 ml) and washed with water, dried over MgSO₄, filtered andconcentrated to give 1-(4-chlorophenyl)-2-(methylsulfanyl)ethanone (5.1gram). ¹H-NMR (CDCl₃, 400 MHz) δ 2.13 (s, 3H), 3.72 (s, 2H), 7.44 (br d,J=8 Hz, 2H), 7.92 (br d, J=8 Hz, 2H).

Ethyl5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate

Sodium metal (2 gram, 87 mmol) was dissolved in ethanol (80 ml). Theresulting solution was added to a magnetically stirred solution ofdiethyl oxalate (6 gram, 41 mmol) and1-(4-chlorophenyl)-2-(methylsulfanyl)ethanone (8.0 g, 40 mmol). Theresulting mixture was reacted for 20 hours at room temperature andsubsequently poured into aqueous hydrochloric acid (200 ml, 1 N). Theresulting mixture was extracted twice with methyl-tert-butyl ether(MTBE) (200 ml), dried over MgSO₄, filtered and concentrated. Theresulting residue was dissolved in acetic acid (200 ml),2,4-dichlorophenylhydrazine.HCl (8.6 gram, 40 mmol) was added and theresulting mixture was heated at 60° C. for 3 hours. The reaction mixturewas allowed to attain room temperature, concentrated to approximately 50ml and poured into water (200 ml), followed by extraction with MTBE (3portions of 150 ml). The combined organic layers were washed with 5%aqueous NaHCO₃, dried over MgSO₄, filtered and concentrated. Furtherpurification using column chromatography (silica gel; eluant:heptane/ethylacetate=90/10 (v/v)) gave ethyl5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate(4.9 gram, 27% yield). R_(f)˜0.4 (heptane/ethylacetate=90/10 (v/v)).¹H-NMR (CDCl₃, 300 MHz) δ 1.44 (t, J=7 Hz, 3H), 2.32 (s, 3H), 4.46 (q,J=7, 2H), 7.10-7.45 (m, 7H).

Lithium5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate

To a magnetically stirred solution of ethyl5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate(4.9 g, 11 mmol) in tetrahydrofuran (100 ml) was added LiOH.H₂O (0.47gram, 11 mmol) and the resulting mixture was reacted for 20 hours at 35°C. and subsequently concentrated in vacuo. The obtained crude lithium5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylatewas used in the next step.

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(pyrrolidin-1-yl)-1H-pyrazole-3-carboxamide(compound 2)

To a magnetically stirred solution of lithium5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate(1.2 gram, 3 mmol maximally) in dimethylformamide (35 ml) wassuccessively added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (1.25 g, 3.9 mmol), triethylamine (1.3 ml) and1-aminopyrrolidine hydrochloride (0.410 gram, 3.35 mmol). After stirringfor 18 h at 50° C. the resulting mixture was allowed to attain roomtemperature and concentrated in vacuo. The remaining residue wastriturated with water and successively further purified by flashchromatography (silica gel, EtOAc/heptane=20/80 (v/v)) to give5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-sulfanyl-N-(pyrrolidin-1-yl)-1H-pyrazole-3-carboxamide:compound 2 (0.78 gram, 54% yield). ¹H-NMR (CDCl₃, 400 MHz) δ 1.88-1.96(m, 4H), 2.39 (s, 3H), 3.02-3.08 (m, 4H), 7.15 (br d, J=8 Hz, 2H),7.29-7.33 (m, 4H), 7.42 (br s, 1H), 7.98 (br s, 1H).

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(azepan-1-yl)-1H-pyrazole-3-carboxamide(compound 3)

Compound 3 was prepared analogously as described for compound 2hereinabove from crude lithium5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate,azepan-1-ylamine, TBTU and Et₃N in DMF in 52% yield.

¹H-NMR (CDCl₃, 400 MHz) δ 1.64-1.68 (m, 4H), 1.72-1.79 (m, 4H), 2.38 (s,3H), 3.18-3.22 (m, 4H), 7.15 (br d, J=8 Hz, 2H), 7.29-7.33 (m, 4H), 7.42(br t, J˜2 Hz, 1H), 8.43 (br s, 1H). ¹³C-NMR (CDCl₃, 100 MHz) δ 20.17,26.30, 26.99, 58.10, 113.31, 126.26, 127.96, 128.75, 130.36, 130.49,131.23, 132.86, 135.62, 135.65, 136.36, 147.26, 147.31, 158.87.

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfonyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide(compound 4)

To a magnetically stirred solution of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide(0.70 gram, 1.41 mmol) was added m-CPBA (2.2 gram of a 70% aqueoussolution, 9 mmol). The resulting mixture was reacted for 70 hours atroom temperature and subsequently poured into water (25 ml). Theresulting mixture was extracted with dichloromethane (25 ml). Theorganic layer was separated and dried over MgSO₄, filtered andconcentrated. Column chromatography (silica gel,dichloromethane/methanol=95/5 (v/v)) gave5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfonyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide(380 mg, 51% yield, compound 4).

¹H-NMR (CDCl₃, 400 MHz) δ 1.70-2.10 (m, 6H), 2.47-2.63 (m, 2H), 3.31 (s,3H), 3.55-3.62 (m, 1H), 3.82-3.90 (m, 1H), 7.12 (br d, J=8 Hz, 2H),7.31-7.36 (m, 4H), 7.42 (d, J=2, 1H), 10.80 (br s, 1H).

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfinyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide(compound 5)

To a magnetically stirred solution of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide(0.70 gram, 1.41 mmol) was added m-chloro-perbenzoic acid (m-CPBA) (0.50gram of a 70% aqueous solution, 2.0 mmol). The resulting mixture wasreacted for 20 hours at room temperature and subsequently poured intowater (25 ml). The resulting mixture was extracted with dichloromethane(25 ml). The organic layer was separated and dried over MgSO₄, filteredand concentrated. Column chromatography (silica gel,dichloromethane/methanol=95/5 (v/v)) gave5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-sulfinyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide(150 mg, 21% yield) (compound 5).

¹H-NMR (CDCl₃, 400 MHz) δ 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H),2.84-2.96 (m, 4H), 3.11 (s, 3H), 7.15 (br d, J=8 Hz, 2H), 7.27-7.32 (m,4H), 7.43 (br s, 1H), 8.70 (br s, 1H). ¹³C-NMR (CDCl₃, 100 MHz) δ 23.28,25.22, 41.84, 56.97, 122.91, 124.67, 128.03, 128.66, 130.41, 130.63,131.60, 133.01, 134.54, 136.51, 136.98, 144.62, 144.85, 157.60.

Example 4 Pharmacological Methods

In vitro affinity for human cannabinoid-CB₁ receptors.

The affinity of the compounds of the invention for cannabinoid CB₁receptors can be determined using membrane preparations of Chinesehamster ovary (CHO) cells in which the human cannabinoid CB₁ receptor isstably transfected in conjunction with [³H]CP-55,940 as radioligand.After incubation of a freshly prepared cell membrane preparation withthe [³H]-ligand, with or without addition of compounds of the invention,separation of bound and free ligand is performed by filtration overglassfiber filters. Radioactivity on the filter is measured by liquidscintillation counting.

In vitro affinity for human cannabinoid-CB₂ receptors.

The affinity of the compounds of the invention for cannabinoid CB₂receptors can be determined using membrane preparations of Chinesehamster ovary (CHO) cells in which the human cannabinoid CB₂ receptor isstably transfected in conjunction with [³H]CP-55,940 as radioligand.After incubation of a freshly prepared cell membrane preparation withthe [³H]-ligand, with or without addition of compounds of the invention,separation of bound and free ligand is performed by filtration overglassfiber filters. Radioactivity on the filter was measured by liquidscintillation counting.

In vitro cannabinoid-CB₁ receptor antagonism.

In vitro CB₁ receptor antagonism can be assessed with the human CB₁receptor cloned in Chinese hamster ovary (CHO) cells. CHO cells aregrown in a Dulbecco's Modified Eagle's medium (DMEM) culture medium,supplemented with 10% heat-inactivated fetal calf serum. Medium isaspirated and replaced by DMEM, without fetal calf serum, but containing[³H]-arachidonic acid and incubated overnight in a cell culture stove(5% CO₂/95% air; 37° C.; water-saturated atmosphere). During this period[³H]-arachidonic acid is incorporated in membrane phospholipids. On thetest day, medium is aspirated and cells are washed three times using 0.5ml DMEM, containing 0.2% bovine serum albumin (BSA). Stimulation of theCB₁ receptor by WIN 55,212-2 lead to activation of PLA₂ followed byrelease of [³H]-arachidonic acid into the medium. This WIN55,212-2-induced release is concentration-dependently antagonized by CB₁receptor antagonists.

CP-55,940 Induced Hypotension in the rat.

Male normotensive rats (225-300 g; Harlan, Horst, The Netherlands) wereanaesthetized with pentobarbital (80 mg/kg i.p). Blood pressure wasmeasured, via a cannula inserted into the left carotid artery, by meansof a Spectramed DTX-plus pressure transducer (Spectramed B. V.,Bilthoven, The Netherlands). After amplification by a Nihon KohdenCarrier Amplifier (Type AP-621 G; Nihon Kohden B. V., Amsterdam, TheNetherlands), the blood pressure signal was registered on a personalcomputer (Compaq Deskpro 386s), by means of a Po—Ne-Mah data-acquisitionprogram (Po—Ne-Mah Inc., Storrs, USA). Heart rate was derived from thepulsatile pressure signal. All compounds were administered orally as amicrosuspension in 1% methylcellulose 30 minutes before induction of theanesthesia which was 60 minutes prior to administration of the CB₁receptor agonist CP-55,940. The injection volume was 10 ml/kg. Afterhaemodynamic stabilization the CB₁ receptor agonist CP-55,940 (0.1 mg/kgi.v.) was administered and the hypotensive effect established.

Example 5 Pharmacological Test Results

Affinity data for human cannabinoid CB₁ and CB₂ receptors (mean resultsof at least three independent experiments, performed according to theprotocols given above) of rimonabant and compounds 1-5 are given in thetable below. These data illustrate the impact on CB₁ and CB₂ receptoraffinities, CB_(1/2) receptor selectivity ratios as well as their invivo potency after oral administration achieved by the structuralmodification that forms the basis of the present invention, and alsoillustrate the CB₁ receptor affinities of the S-oxidized compounds 4 and5.

TABLE 1 CB₁ and CB₂ receptor affinities and in vivo activity in CBreceptor-mediated rat model of rimonabant and compounds 1-3 of thisinvention and CB₁ receptor affinities for the S-oxidized compounds 4 and5; nd = not determined. hCB₁ hCB₂ CB₁/CB₂ Blood pressure (rat) compoundX Y n K_(i)(nM) K_(i)(nM) ratio ED₅₀ (mg/kg, p.o.) rimonabant CH₂ H 2 251580 63 3.2 Comp. 1 S CH₃ 2 10 668 67 1.5 Comp. 2 S CH₃ 1 <10 340 >341.9 Comp. 3 S CH₃ 3 20 500 25 3.1 Comp. 4 S═O CH₃ 2 13 nd — nd Comp. 5SO₂ CH₃ 2 250 nd — nd

Example 6 Pharmaceutical Preparations

For clinical use, compounds of formula (I) are formulated into apharmaceutical compositions that are important and novel embodiments ofthe invention because they contain the compounds, more particularlyspecific compounds disclosed herein. Types of pharmaceuticalcompositions that may be used include, but are not limited to, tablets,chewable tablets, capsules (including microcapsules), solutions,parenteral solutions, ointments (creams and gels), suppositories,suspensions, and other types disclosed herein or apparent to a personskilled in the art from the specification and general knowledge in theart. The compositions are used for oral, intravenous, subcutaneous,tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal,parenteral or other ways to administer. The pharmaceutical formulationcontains at least one compound of formula (I) in admixture with apharmaceutically acceptable adjuvant, diluent and/or carrier. The totalamount of active ingredients suitably is in the range of from about 0.1%(w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50%(w/w) and preferably from 1% to 25% (w/w). The compounds of theinvention can be brought into forms suitable for administration by meansof usual processes using auxiliary substances such as liquid or solid,powdered ingredients, such as the pharmaceutically customary liquid orsolid fillers and extenders, solvents, emulsifiers, lubricants,flavorings, colorings and/or buffer substances. Frequently usedauxiliary substances include magnesium carbonate, titanium dioxide,lactose, saccharose, sorbitol, mannitol and other sugars or sugaralcohols, talc, lactoprotein, gelatin, starch, amylopectin, celluloseand its derivatives, animal and vegetable oils such as fish liver oil,sunflower, groundnut or sesame oil, polyethylene glycol and solventssuch as, for example, sterile water and mono- or polyhydric alcoholssuch as glycerol, as well as with disintegrating agents and lubricatingagents such as magnesium stearate, calcium stearate, sodium stearylfumarate and polyethylene glycol waxes. The mixture may then beprocessed into granules or pressed into tablets.

The active ingredients may be separately premixed with the othernon-active ingredients, before being mixed to form a formulation. Theactive ingredients may also be mixed with each other, before being mixedwith the non-active ingredients to form a formulation.

Soft gelatine capsules may be prepared with capsules containing amixture of the active ingredients of the invention, vegetable oil, fat,or other suitable vehicle for soft gelatine capsules. Hard gelatinecapsules may contain granules of the active ingredients. Hard gelatinecapsules may also contain the active ingredients together with solidpowdered ingredients such as lactose, saccharose, sorbitol, mannitol,potato starch, corn starch, amylopectin, cellulose derivatives orgelatine. Dosage units for rectal administration may be prepared (i) inthe form of suppositories that contain the active substance mixed with aneutral fat base; (ii) in the form of a gelatine rectal capsule thatcontains the active substance in a mixture with a vegetable oil,paraffin oil or other suitable vehicle for gelatine rectal capsules;(iii) in the form of a ready-made micro enema; or (iv) in the form of adry micro enema formulation to be reconstituted in a suitable solventjust prior to administration.

Liquid preparations may be prepared in the form of syrups, elixirs,concentrated drops or suspensions, e.g. solutions or suspensionscontaining the active ingredients and the remainder consisting, forexample, of sugar or sugar alcohols and a mixture of ethanol, water,glycerol, propylene glycol and polyethylene glycol. If desired, suchliquid preparations may contain coloring agents, flavoring agents,preservatives, saccharine and carboxymethyl cellulose or otherthickening agents. Liquid preparations may also be prepared in the formof a dry powder, reconstituted with a suitable solvent prior to use.Solutions for parenteral administration may be prepared as a solution ofa formulation of the invention in a pharmaceutically acceptable solvent.These solutions may also contain stabilizing ingredients, preservativesand/or buffering ingredients. Solutions for parenteral administrationmay also be prepared as a dry preparation, reconstituted with a suitablesolvent before use.

Also provided according to the present invention are formulations and‘kits of parts’ comprising one or more containers filled with one ormore of the ingredients of a pharmaceutical composition of theinvention, for use in medical therapy. Associated with such container(s)can be various written materials such as instructions for use, or anotice in the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals products, which noticereflects approval by the agency of manufacture, use, or sale for humanor veterinary administration. The use of formulations of the presentinvention in the manufacture of medicaments for use in treating acondition in which antagonism of cannabinoid-CB₁ receptors is requiredor desired, and methods of medical treatment or comprising theadministration of a therapeutically effective total amount of at leastone compound of formula (I), either as such or in the case of prodrugs,after administration, to a patient suffering from, or susceptible to, acondition in which antagonism of cannabinoid-CB₁ receptors is requiredor desired.

We claim:
 1. A method for treating at least one disorder in a patient inneed thereof, wherein said at least one disorder is chosen frompsychosis, anxiety, depression, attention deficits, memory disorders,cognitive disorders, appetite disorders, obesity, addiction, appetence,drug dependence, dementia, dystonia, muscle spasticity, tremor,epilepsy, multiple sclerosis, traumatic brain injury, stroke,Parkinson's disease, Alzheimer's disease, epilepsy, Huntington'sdisease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy,craniocerebral trauma, stroke, spinal cord injury, neuroinflammatorydisorders, plaque sclerosis, vital encephalitis, demyelinisation relateddisorders, neuropathic pain disorders, septic shock, glaucoma, diabetes,emesis, nausea, asthma, respiratory diseases, gastrointestinaldisorders, gastric, ulcers, diarrhoea, and sexual disorders, said methodcomprising administering to the patient a pharmacologically effectiveamount of at least one compound of formula (I),

wherein: R₁ represents H, Cl or Br, R₂ represents Cl or Br, X representsa sulphur atom, a sulfoxide (S═O) or a sulfone (SO₂) moiety, Yrepresents a methyl or an ethyl group, and n can have the value 1, 2 or3, or a tautomer, stereoisomer, prodrug or N-oxide thereof, or apharmacologically acceptable salt of said compounds of formula (I), or atautomer, stereoisomer, or N-oxide of any of the foregoing.
 2. Themethod as claimed in claim 1, wherein the at least one disorder ischosen from appetite disorders and obesity.
 3. The method as claimed inclaim 2, wherein the at least one disorder is obesity and is chosen fromjuvenile obesity and drug induced obesity.
 4. The method as claimed inclaim 2, further comprising administration of at least one lipaseinhibitor.
 5. The method as claimed in claim 4, wherein said lipaseinhibitor is orlistat or lipstatin.